Fig 2: Cartoon representation based on our studies and literature information, depicting the possible signalling mechanism induced by monotherapy (LD8Δ) and combination therapy (LD8Δ + HIF-2α siRNA). Green pointed arrows indicate upregulation and red blunt arrows indicate downregulation. * indicates information supported by well-known scientific literature. The left panel shows both LD8Δ as monotherapy and LD8Δ and HIF-2α gene silencing as combination therapy upregulated VHL. VHL ubiquitinates both HIF-2α and RAPTOR, leading to the proteosome-mediated degradation of both the proteins, thus inhibiting both HIF-2 (HIF-2α + HIF-β) and mTOR signalling pathways, simultaneously. Inhibition of HIF signalling led to the downregulation of VEGF, CD47, PD-L1 and GM2 gangliosides, resulting in reduced angiogenesis, increased phagocytosis, T cell activation and prevention of T cell apoptosis, respectively. Inhibition of mTOR signalling led to reduced cell proliferation. The right panel indicates that the combination therapy of LD8Δ and HIF-2α gene silencing upregulated the DAB2IP protein, leading to radiosensitization of the metastatic ccRCC cell line SK-RC-45.